Enhanced method for delivering bevacizumab (avastin) into a brain tumor using an implanted magnetic breather pump

ABSTRACT

A magnetically controlled pump is implanted into the brain of a patient and delivers a plurality of medicating agents mixed with Avastin at a controlled rate corresponding to the specific needs of the patient. The current invention comprises a flexible double walled pouch that is formed from two layers of polymer. The pouch is alternately expanded and contracting by magnetic solenoid. When contracted, the medicating agent Avastin is pushed out of the pouch through a plurality of needles. When the pouch is expanded, surrounding cerebral fluid is drawn into the space between the double walls of the pouch from which it is drawn through a catheter to an analyzer. In cases where a tumor resection is not performed, an intratumoral catheter will be implanted. Cerebral fluid drawn from the patient is analyzed. The operation of the apparatus and hence the treatment is remotely controlled based on these measurements and displayed through an external controller.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to the field of implantable drug delivery systems,specifically a magnetically controlled aspirating pump and a method fordelivering the anti-angiogenesis agent Bevacizumab (Avastin) into abrain tumor using the same.

2. Description of the Prior Art

When tumors develop inside the human body, the options for availabletreatment are fairly narrow. This is even more so when the tumordevelops inside a vital organ such as the brain. Diseases such as braincancer, i.e. malignant gliomas, and other cancers that develop in oraround the brain are notoriously difficult to treat and thus have a highmortality rate. The invention described herein is directed specificallyfor malignant gliomas; however, it is applicable to all types ofmalignant tumors where local control is desired with direct intratumoraltreatment with Avastin.

Traditionally, the options for treating a tumor located in or on thebrain include surgery, radiation, chemotherapy, and local intratumoraltherapy. Each of these prior methods of treating a brain tumor have hadsome form of success in the past, however each of them also containvarious deficiencies and pitfalls that make them less than ideal whentreating a patient. What is needed is a more reliable, easier, andeffective process for treating a malignant brain tumor.

The oldest and most direct way for treating a brain tumor is to removeit surgically. Surgery is effective in obtaining tissue diagnosis andremoving the mass effect of the tumor from the adjacent normal brain.However, it is invasive, expensive, and poses potential surgicalcomplications for the patient. Most importantly, surgery cannot cure amalignant brain tumor, as the cancer cells have often invaded far intothe normal brain when the diagnosis is first confirmed. Additionally,surgery is only available when the tumor is in a surgically accessiblelocation. Tumors located deep within the brain are often inoperable asthe surgery would significantly impair the patient's neurologicalfunction. Even if surgery is possible, there is still a chance of braindamage and an extremely long recovery time associated with surgery.

Radiation is the next mode of treatment for brain cancer. It is usuallygiven as a fractionated dosage treatment, covering a certain fieldencompassing the tumor, over a period of six weeks. Spatially localizedforms of radiation, including cyberknife and gamma knife have been usedwith varying levels of success. Although radiation is still widelyacknowledged as the most effective mode of adjunctive treatment for amalignant brain tumor, it suffers from the disadvantage of limitedfractions and applications, as the brain can only be radiated so muchwithout developing severe sequelae.

The third method used to combat brain tumors is systemic chemotherapy.Systemic chemotherapy is a viable option as an adjunct to radiation andsurgery. However, it is limited in efficacy in brain cancers by: 1)delivery across the blood brain barrier, 2) development of drugresistance by the cancer cells, and 3) systemic side-effects from thechemotherapeutic agent. Because the blood brain barrier is onlypartially broken down in the presence of a malignant brain tumor, itstill impairs the effective delivery and transport of systemicchemotherapy into the brain cancer. Secondly, brain tumors can developdrug resistance. As a result, the cancer learns how to avoidcytotoxicity of the delivered drug. Lastly, chemotherapy is distributedsystemically throughout the entire body. Because the whole body of thepatient undergoes the treatment (not just the tumor and the tumorrelated area), undesirable side effects such as nausea, diarrhea, hairloss, and loss of appetite and energy may occur. Some of the sideeffects are so strong in some patients that chemotherapy is unavailableto them as a treatment and thus decrease their overall chances forsurvival.

The anti-angiogenesis agent Avastin is currently FDA approved for thetreatment of recurrent glioblastoma multiforme (GBM). It is an antibodywhich is capable of binding to vascular endothelial growth factor(VEGF), the angiogenesis agent secreted by glioma cells, and isresponsible for binding to the endothelial cells in the glioma, causingthe blood vessels to proliferate and vascularize the glioma. It iscurrently administered via intravenous administration every two weeks,and is given as a stand-alone drug. No clear benefit has been documentedfor combination of Avastin with standard cytotoxic chemotherapy ieirinotecan (CPT-11). Because of the anti-angiogenesis nature of Avastin,it would be more effective when given on a continuous metronomicdelivery. However, because of its need for intravenous administration,it is impossible to deliver it on a continuous basis. Moreover, becauseAvastin is an antibody, it is not capable of effectively crossing theblood brain barrier. Instead, it only binds to the VEGF present in theluminal side of the blood vessel. Intravenous Avastin is associated witha number of systemic side-effects including poor wound healing, deepvenous thrombosis, renal toxicity, and threat of intracerebralhemorrhage. On the other hand, intratumoral Avastin would not beaffected by these systemic complications, including poor wound healing.

The last major method of treating brain tumors has been the applicationof various local intratumoral therapies. These therapies includechemotherapy wafers, stereotactic injections, and convection enhanceddeliveries. All of these treatment therapies involve directly infusingthe tumor with an appropriate drug regimen; however this method too isnot without its limitations. Chemotherapy wafers (Gliadel) are currentlylimited by only one drug available (BCNU), and by its diffusioncapability of only a few millimeters away from the tumor bed.Stereotactic injections of chemotherapy have also been applied. However,only one injection is available at any single time. If another injectionis needed, then another stereotactic surgical injection would have to beperformed. Moreover, the spread of the chemotherapy is limited to theinjection site and some of the adjacent normal brain. Lastly, convectionenhanced delivery via an external micropump has been used to increasethe circumference of drug delivery. It is usually given by anexternalized catheter, and the drug is delivered for a cycle of 4-6days. At the end of that time, the catheter will have to be removed. Ifthe drug is to be delivered again, another surgical procedure forconvection enhanced delivery will have to be performed. This can be veryexpensive and painful as some intratumoral therapies involve exposingthe brain to an externalized catheter for long periods of time orcomplicated implantations of temporary catheters and other medicaldevices. Additionally, many of the previous intratumoral therapies areineffective and do not significantly enhance or lengthen the life of apatient receiving such treatment.

The underlying hypothesis of using polypharmacy employed by the currentinvention is based on the premise that combination therapy is oftenbetter than monotherapy. Thus, a first step in administrating acytotoxic agent is to determine the maximum tolerated dose (MTD).However, when used in traditional treatment mores, such as chemotherapy,the cytotoxic agents are delivered to the patient in a manner thatallows the cytotoxic agents to be distributed more or less globallythroughout the body of the patient. Relatively large doses of the drugsare required since only a small fraction of the administered dose willbe present at the tumor site at any given time. The remainder of thedose will be in the other parts of body. Moreover, a major problem withconventional chemotherapy is lack of specificity in targeting the cancercell.

The use of large doses of toxic agents often leads to serious anddebilitating side effects. Moreover, the global administration of drugsis often not compatible with combination therapies where a number ofmedicating agents are used synergistically to treat tumors or otherconditions. Thus, the global administration of medicating agents totreat tumors and other such medical conditions is an inefficient andoften dangerous technique that often leads to severe or debilitatingside effects.

The use of intratumoral Avastin has never been used in the humanpopulation. Considerations of intracerebral hemorrhage and lack of aneffective delivery device have been factors inhibiting its use. From atreatment standpoint, intratumoral Avastin does have the advantage ofcontinuous metronomic delivery, delivery to the glioma cells that areactually secreting VEGF (not just the luminal side of the blood vesselas in intravenous delivery), and potentially much lower amounts ofAvastin needed to be effective. Recent experiments performeddemonstrated that Avastin does not induce an intracerebral orintratumoral hemorrhage when administered intratumorally in anintracranial rodent model. Moreover, there was no increased evidence ofan immune response from infusion of an antibody such as Avastin. Mostimportantly, we demonstrated that the survival time of these animals wassignificantly prolonged with intratumoral Avastin compared tointravenous Avastin as seen in FIG. 18.

Local administration of an anti-VEGF antibody has been employed by Roche(formerly Avastin) for macular degeneration. Studies have shown that itmay be administered safely locally. However, intratumoral delivery ofAvastin has never been shown in either in-vivo animal studies or humanstudies.

Recently, there have been some developments in the field of medical drugdelivery systems. The majority of these systems have taken the form of apump or other device that releases a variety of drugs into variouspositions in and around the body of a patient.

For example, many of the devices found in the prior art are much likethe inventions disclosed in U.S. Pat. No. 6,852,104 (“Blonquist”) andU.S. Pat. No. 6,659,978 (“Kasuga”). Both of these inventions comprise asmall tank for holding a drug regimen, a pump for pumping the drugregimen into the body of a patient, and some sort of electronic controlsystem that allows the user to program the specific amount and at whattime a certain drug regiment is to be administered. While theseapparatus may be ideal for administering certain drugs such as insulinto patients who are diabetic, they are neither designed nor suitable fordirectly treating a tumor within the brain of a patient.

Other prior art examples such as U.S. Pat. No. 5,242,406 (“Gross”) andU.S. Pat. No. 6,571,125 (“Thompson”) offer smaller, more convenientalternatives for administering drugs, however their reliance onmaintaining a specific set of pressures and a certain amount ofelectrical current respectively makes them too complicated and prone toerror.

U.S. Pat. No. 7,351,239 (“Gill”), U.S. Pat. No. 7,288,085 (“Olsen”), andU.S. Pat. No. 6,726,678 (“Nelson”) disclose a pump or reservoir that iscapable of delivering medicating fluids to the brain, but requires thatthe pump and drug reservoir be implanted in different locations withinthe patient. This configuration is not only uncomfortable for thepatient, but also increases the possibility of infection andunnecessarily complicates the implanting procedure. Additionally, everytime the patient needs the drug reservoir refilled or the pump batteryreplaced, the physician must invasively re-enter the-patient. Finally,none these prior methods disclose a way of measuring the value of thevascular endothelial growth factor (VEGF) so as to enable tailoring ofthe delivered medical agent, toxicity to meet the needs of a specificindividual patient.

What is needed is a device and a method that is capable of deliveringmedicating agents directly to a tumor located in the brain of a patientthat is easy to operate and relatively simple to implant, while at thesame time, is easy to maintain throughout the patient's treatment cycleand customize to the patient's specific needs without causing all of thenegative side effects associated with previous treatment methods.

The combination of Avastin with the MBP allows for an unique combinationof drug and device, enabling a new combination to be used in thetreatment of malignant gliomas.

BRIEF SUMMARY OF THE INVENTION

A magnetically controlled pump is implanted into the brain of a patientand delivers a dose of Avastin at a controlled rate corresponding to thespecific needs of the patient. The current invention comprises aflexible double walled pouch that is formed from two layers of polymer.The pouch is alternately expanded and contracting by magnetic solenoid.When contracted, Avastin is pushed out of the pouch through a pluralityof needles. When the pouch is expanded, surrounding cerebral fluid isdrawn into the space between the double walls of the pouch from which itis drawn through a catheter to an analyzer. Cerebral fluid drawn fromthe patient is analyzed. The operation of the apparatus and hence thetreatment is remotely controlled based on these measurements anddisplayed through an external controller.

The illustrated embodiment of the invention solves the above limitationsin the prior art and other problems by effectively treating brain tumorsusing a magnetically controlled pump implanted into the tumor resectioncavity or a multi-delivery catheter implanted into an unresectabletumor, i.e. a tumor in which a surgical removal of all or part of anorgan, tissue, or structure is not practically feasible. Through bothproximal ports, an internalized externally controlled pump will deliverup to four different kinds of chemotherapeutic agents, including thedrug Avastin, at a controlled rate corresponding to the specific needsof the patient.

The microdelivery pump has three components: a proximal head implantedinto the tumor, a catheter extending from the proximal head, and ananalyzer unit connected to the catheter. The proximal head is eithercomprised of a catheter inserted into the tumor or a magnetic breatherpump. Which type of proximal head is employed depends on whether a tumorcavity is available. If a tumor is considered unresectable or if thepatient does not want open surgery, only a catheter only will beimplanted. However, if a resection is performed, then different sizemagnetic breather pumps can be inserted into the tumor cavity, dependingon its volume. The entire unit is self-contained and entirelyinternalized.

Briefly, the illustrated embodiment of the invention comprises aproximal delivery device which will be implanted into the patient'sbrain tumor. A first embodiment is made for patients who have had asurgical resection, with a resultant tumor cavity. In those cases, asmall, round flexible pouch that is formed from two layers of polymermaterial is implanted. At the head and base caps of the pouch areelectromagnetic coils that, when activated, are alternately attractedand repelled from each other thus causing the pouch to contract andexpand. The inner layer of polymer material acts as a reservoir forAvastin or a mixture of several medicating agents including Avastin. Theinner layer also contains a plurality of polymer needles on its surfacethat allow the medicating agent to pass through the outer polymer layerand deep into the surrounding tissue of the patient, when the pouch iscontracted by the electromagnetic coils. The outer polymer layer isporous which allows surrounding cerebral fluid to be drawn into thepouch from the suction that is created when the pouch is expanded by theelectromagnetic coils. This mechanical aspiration and exchange of fluidsby the pouch is then repeated until the entire amount of Avastin hasbeen delivered, or until a preselected time period has expired.

The head cap of the pouch also contains a valve that allows thereservoir of the apparatus to be refilled and for cerebrospinal fluidthat has been drawn into the pouch to be withdrawn from the cranium ofthe patient via a suction nozzle. In this way, the pump also enables adecompressive mechanism for controlling the intratumoral pressure, andfor sampling fluid.

In patients in whom a resection cannot be performed, an alternativeembodiment of the current invention involving a multidelivery catheteris employed. Conventional catheters used for convection enhanceddelivery for brain tumors consist of either a single port in the tip ofperitoneal tubing used for ventriculoperitoneal shunts, or a proximalshunt catheter with multiple holes cut within 1 cm of the tip ofcatheter tip. The multidelivery catheter described herein is comprisedof a catheter tip from which a balloon with multiple spines emergesunder positive pressure from the pump.

The medication intake line and the cerebrospinal fluid return linecoupled to the head cap of the apparatus are housed within a siliconecatheter. The catheter runs underneath the scalp of the patient, aroundthe back of the head, and emerges from the patient in an easilyaccessible location such as beneath the head of the clavicle as in aPort-A-Cath. The catheter is coupled to an analyzer unit, thus couplingthe aspirating pump to a control device and forming a drug deliverysystem.

The analyzer unit is a housing means for several key components of theapparatus. Cerebrospinal and/or tumor fluid that has returned from thepatient passes through a lab-on-a-chip which measures and monitors thevascular endothelial growth factor (VEGF) levels for indications ofprogress or regression of the patient's tumor burden. The user orphysician operating the apparatus can then adjust or change the drugregimen the patient is receiving based on these measurements. Alsocoupled to the unit are four piezo pumps that send up to four differentmedicating agents, one of which being the drug Avastin, through thecatheter and into the reservoir of the implanted pouch. A Blue Tooth®chip also allows the unit to be controlled by a physician from a remotelocation. Flash memory chips and an artificial intelligence processorcomplete the circuitry needed in order to provide the patient with aneffective, easy to use apparatus that delivers medicating agents at aset and controlled rate. Finally, the analyzer unit or chemotherapypumping device (CPD) includes a long lasting lithium ion battery thatpowers the unit itself.

It is therefore an object of the invention to provide a patient withconstant medication without re-implanting a catheter every time apatient needs to be treated.

It is another object of the invention to provide a metronomic continuousdelivery of a medicating agent.

It is a further object of the invention to provide users and physiciansin charge of a patient's treatment instant monitoring and feedback ofvarious tumor parameters in order for the patient's treatment to bechanged or adjusted accordingly.

It is a further object of the invention to provide patients with braintumors an effective way of treating their affliction while minimizingthe side effects of chemotherapy.

Another object of the invention is to enhance the mechanism of vectorialchange of tumor escape mechanism by introducing a sufficient tumorantigen to stimulate the immune system of the patient.

Another object of the invention is to assist in irrigating the solidtumor by increasing cell adhesion molecules which are used for theadherence of cytotoxic cells to target cells before lysis can ensue. Themalignant cells cannot bind to cytotoxic cells. The use of the apparatuswill improve and enhance such a process.

Yet another object of the invention is to administrate biologicalresponse modifiers (BRMs) with an improved dose, local delivery andscheduling on a case-specific basis using the programmablemicrocontroller and its associated valve mechanism.

Another object of the invention is to allow the clinician the ability toprescribe an optimal biological dose (OBD) of Avastin as opposed tomaximum tolerated dose (MTD) of Avastin by the use of an apparatuscontrol mode defined by its programmability and its logic, which isembedded in microcontroller look-up-tables.

Another object of the invention is to incorporate the pharamacokineticand pharmacodynamic parameters associated with chemotherapeutic agentsso as to achieve the desired results without the toxic side effectsknown to those familiar with the art.

Another object of the invention is to modulate and modify the output ofthe Avastin during treatment by changing the procedure in real timethrough the use of the command structure of the microcontrollerlook-up-tables with the use of a communication link built into theapparatus.

Another object of the invention is to regulate the rate of dispensationof the Avastin by modifying the duty cycle of the valve located in theapparatus.

Another object of the invention is to regulate the intake of the tumorBRMs due to their pleiotropic nature, and allow for processes andmechanisms to develop by reducing or enhancing the various agents in themedicating apparatus (MBP), hence providing a treatment specific to thepatient (e.g. tumor, size, lysis, etc).

Another object of the invention is to provide the clinician a way toallow the expression of BRMs cascade effects (due to the communicationof cytokines as messengers with their synergistic, additive orantagonistic interactions that affect the target tumor cells).

Another object of the invention is to provide scheduling of medicatingagents such as cyototoxic chemotherapy, BRMs, and Avastin as based ontheir toxicity, and to allow for measures such as bioavailability,solubility, concentration, and circulation based on locality, both ofwhich are the improved approach to the elimination of solid tumors.

Another object of the invention is to address the individual differencesof various tumors based on the disease stage, immune factors, bodyweight, age and chronobiology through the ability of the apparatus tolocally administer the agents, dosing, and scheduling.

Another object of the invention is to provide an effective mode ofadministrating BRMs with chemotherapy as a combination therapy by makingavailable a local administration of different IFNs with IL-2 or IL-2 incombination with monoclonal antibodies and tumor necrosis factors(TFNs), and scheduling by the use of the invention under metromonicregiment.

Another object of the invention is to enable drug manufacturers toevaluate the effectiveness of its drug during animal and clinicalstudies by providing the details and feedback on the use, dose, cycle,circadian time effects and the entire pharmacokinetic andpharmacodynamic behavior of the medicating agents not as verbal reportsof symptomalogy chronicles by the patient, but as a biological measureof tumor responses to the agents.

Another object of the invention is to provide a method and apparatus forlocal administration of BRMs, cytotoxic chemotherapeutic agents, andAvastin, to enhance mechanisms that support overlapping effects inreducing tumor burden and elimination of tumors. To induce an improvedresponse by the use of biomodulators (augmenting the patient'santi-tumor response via production of cytokines), decreasing suppressormechanisms, increasing the patient's immunological response, limitingthe toxicity of such agents (by the locality), maximizing the dose,increasing susceptibility of cells membrane characteristics for improvedchemotherapy results at the site, and decreasing the tumor's, ability tometastasize.

The above characteristics are measurable elements since dosing andscheduling improves the effectiveness of chemotherapy on malignant cellsand reduces the exposure of such toxins to normal tissues. Oneembodiment provides improved immunomodulation with relatively littleimmuno-suppression.

Another object of the invention is to provide for defining an improveddose and schedule of biological agents to maximize the anti-tumoreffects of each agent while not increasing toxicity to the patient.Treatment modality by the use of combination therapy and localadministration of such agents on a specific schedule is one of thebenefits of the invention.

It is yet another object of the invention to provide operatingphysicians a method of treating brain tumors without having to worryabout Avastin being diluted or hindered by the blood brain barrier (i.e.direct antibody injection into the tumor).

Finally, it is yet another object of the invention to providepreoperative simulation of the infusion of Avastin and otherintratumoral infusates to maximize infusion efficiency and minimizelocal toxicity to the adjacent brain from leakage of the infusate intothe normal tissue. The diffusion model permits a systematic design oftargeted drug delivery into the human brain by predicting achievablevolumes of distribution for therapeutic agents based on the establishedtransport and chemical kinetics models. The model can be simulated in acomputer-aided brain analysis before the actual placement procedure,thus reducing the need for trial-and-error animal experimentation orintuitive dosing in human trial, maximizing preoperative planning, andminimizing intraoperative and postoperative complications.

While the apparatus and method has or will be described for the sake ofgrammatical fluidity with functional explanations, it is to be expresslyunderstood that the claims, unless expressly formulated under 35 USC112, are not to be construed as necessarily limited in any way by theconstruction of “means” or “steps” limitations, but are to be accordedthe full scope of the meaning and equivalents of the definition providedby the claims under the judicial doctrine of equivalents, and in thecase where the claims are expressly formulated under 35 USC 112 are tobe accorded full statutory equivalents under 35 USC 112. The inventioncan be better visualized by turning now to the following drawingswherein like elements are referenced by like numerals.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 a is a diagrammatic cross sectional view of a patient's bodyafter the implantable pump unit has been successfully implanted into thetumor cavity and placed under the patient's skull and dura and the CPDhas been implanted beneath the skin in the chest cavity.

FIG. 1 b is a block diagram of the architecture of the external controlunit which communicates with the implanted apparatus.

FIG. 1 c is a diagram which illustrates the implantable pouch and itsassociated communications controller.

FIG. 2 is an isometric view of the CPD.

FIG. 3 a is a front view of the CPD.

FIG. 3 b is a left side view of the CPD.

FIG. 3 c is a right side view of the CPD.

FIG. 3 d is a bottom view of the CPD.

FIG. 4 a is a right side view of the CPD highlighting the deliveryconnector.

FIG. 4 b is a magnified view of the delivery connector of FIG. 4 a.

FIG. 4 c is a bottom view of the CPD with an ampoule bay highlighted.

FIG. 4 d is a magnified view of an ampoule bay of FIG. 4 c.

FIG. 5 is a partially exploded view of the CPD.

FIG. 6 is a fully exploded view of the CPD.

FIG. 7 a is a perspective view of the top of the induction chargerassembly and pump electronics assembly coupled together.

FIG. 7 b is a perspective view of the bottom of the induction chargerassembly and pump electronics assembly coupled together.

FIG. 8 a is a perspective view of the top of the pump electronicsassembly.

FIG. 8 b is a perspective view of the bottom of the pump electronicsassembly.

FIG. 9 a is a perspective view of the top of the induction chargerassembly.

FIG. 9 b is a perspective view of the bottom of the induction chargerassembly.

FIG. 10 a is an isometric view of the implantable cranium pump.

FIG. 10 b is a diagram which depicts the “electrostatic muscle” definingthe “supply mode” of the implantable cranium pump.

FIG. 10 c is a diagram which depicts the “electrostatic muscle” definingthe “pump mode” of the implantable cranium pump.

FIG. 11 a is an isometric view of the implantable cranium pump with thepump-to-seal interconnect disconnected.

FIG. 11 b is a magnified view of the pump head assembly.

FIG. 12 is a cross sectional view of the implantable cranium pump.

FIG. 13 a is a partially cutaway cross sectional view of the implantablecranium pump with a polarity of injector spines highlighted.

FIG. 13 b is a magnified view of the injector spines in the circledregion 13 a of FIG. 13 a.

FIG. 13 c is a magnified cross sectional view of the inner and outermembranes of the implantable cranium pump.

FIG. 14 a is a side and cross sectional view of a hollow injectorneedle.

FIG. 14 b is a side and cross sectional view of a spiral injectorneedle.

FIG. 15 a is a front view of the pump actuator assembly.

FIG. 15 b is a cross sectional view of the pump actuator assembly.

FIG. 16 a is an exploded bottom view of the pump actuator assembly.

FIG. 16 b is an exploded top view of the pump actuator assembly.

FIG. 17 is a functional block diagram of the pump actuator assembly.

FIG. 18 is a graph of the results of a study conducted using miceimplanted with glioma cells and treated with chemotherapeutic agents(including intratumoral Avastin) both systemically and via an implantedcranium pump, demonstrating superior survival in mice treated withintratumoral Avastin or intratumoral Avastin and CPT-11, compared tointravenous Avastin with or without CPT-11

The invention and its various embodiments can now be better understoodby turning to the following detailed description of the preferredembodiments which are presented as illustrated examples of the inventiondefined in the claims. It is expressly understood that the invention asdefined by the claims may be broader than the illustrated embodimentsdescribed below.

DEFINITIONS

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the methods, devices,and materials are now described. All publications mentioned herein areincorporated herein by reference for the purpose of describing anddisclosing the materials and methodologies which are reported in thepublications which might be used in connection with the invention.Nothing herein is to be construed as an admission that the invention isnot entitled to antedate such disclosure by virtue of prior invention.

The following mathematical symbols used here in refer to its definitionsas follow: Q is infusate flow rate; ρ is fluid density; {right arrowover (ν)}_(f) is fluid velocity vector in the catheter; μ is fluidviscosity; ε is tissue porosity; p is infusion fluid pressure; {rightarrow over (∇)}p is pressure gradient; D_(b) is bulk diffusivity;D_(e)is effective diffusion tensor; C_(f)=Concentration of drug; {rightarrow over (ν)}_(t) is flud velocity in the porous tissue; D_(e) is meaneffective diffusivity; k is first order rate constant accounting fordrug reaction;

Hydraulic conductivity tensor, which is a function of fluid viscosity μand effective tissue permeability tensor κ; {right arrow over(ν)}_(t)·{right arrow over (∇)}C_(t)is convection term; D_(e){rightarrow over (∇)}C_(t) is diffusion flux; C_(t)({right arrow over (x)}, t)is tissue averaged species concentration; R(C_(t), {right arrow over(x)}) is drug decomposition due to metabolic reaction; and S(C_(t),{right arrow over (x)}) is sink term due to bio-elimination.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The apparatus is additionally described and disclosed within U.S. patentapplication Ser. No. 12/143,720 filed Jun. 20, 2008, which is hereinincorporated by reference in its entirety.

The implantable cranium pump unit 100 of the illustrated embodiment ofthe invention depicted in. FIG. 10 a comprises of two distinct polymerlayers; an inner membrane 107 and the outer membrane 106 as best seen inFIG. 13 c. Inner membrane 107 and outer membrane 106 are seamed togetherat the base and head of cranium pump 100 by a pump solenoid assembly 104and a pump head assembly 103 respectively (FIG. 12). The pump solenoidassembly 104 and pump head assembly 103 provide a means for contractingand expanding the cranium pump 100 and are further discussed in moredetail below. Both inner membrane 107 and outer membrane 106 are madefrom a skin-like polymer material. This material allows the pump 100 tobe highly flexible during the drug delivery process and decreases thechances for infection or rejection from the body of a patient.

The space enclosed by inner membrane 107 is a medication reservoir 129used for storing the drug Avastin or a mixture of medicating agents withAvastin as shown in FIG. 12.

Avastin is manufactured by Genetech Inc., a subsidiary of Roche HoldingAG. Avastin is a monoclonal antibody to vascular endothelial factor(VEGF) and is currently approved by the FDA for recurrent malignantgliomas. Briefly, Avastin works on the premise that malignant tumorssuch as gliomas secrete VEGF, when then binds to the glioma endothelialcells. Avastin, by mopping up the VEGF, acts as an anti-angiogenesisagent. Typically Avastin is given intravenously every two weeks to apatient, however a variety of complications including poor woundhealing, kidney damage, intracerebral hemorrhage, and venous thrombosishave been associated with such treatment. While Avastin has only beenadministered via intravenous means, promising new research suggests thatdirect intratumoral administration would be even more effective intreating tumors and less catastrophic for the patient. Such directintratumor implementation would only be possible with the use of theabove disclosed pump 100.

The size and volume of the medication reservoir 129 and thus the craniumpump 100 itself may be varied from patient to patient. A physician willmake a determination of how much medication a particular patient willneed and then the size of the medication reservoir 129 will be madeaccordingly. For example, a patient that needs large doses of medicationwill receive a cranium pump 100 with a larger medication reservoir 129then a patient who only requires a small dose.

Turning again to FIGS. 13 a-13 c, the inner membrane 107 furthercomprises a plurality of small injector spines 108 distributedthroughout the entire surface of the inner membrane 107. As can be seenin FIGS. 14 a and 14 b, the injector spines 108 may be comprised ofhollow tubes 109 or a spiral design 133 with a pleated inlet 110 at itsbase where spine 108 meets the inner membrane 107 (FIG. 13 c). The innermembrane 107 has a shape memory which effectively causes it to act astelescoping springs to rapidly extend and retract the injector spines108 through the surface of the outer membrane 106. The injector spines108 are also sufficiently long enough to penetrate the outer membrane106 when the cranium pump 100 is in its most expanded state as shown inFIG. 10 a. The injector spines 108 are tapered at their tips so thatfluid flows substantially in only one direction, namely from themedication reservoir 129 to the surrounding tissue of the patient.

When the cranium pump 100 is being contracted or is in its supplystroke, the inner membrane 107 is pushed outward thus extending theinjector spines 108 further past the outer membrane 106 and deeper intothe patient's surrounding tissue. This process allows the pump 100 todeliver Avastin deeper into the affected tissue and thus the tumoritself in a more direct way than any prior art method. The injectorspines 108 extend into the patient's tissue and the increased pressurecreated by the contracting cranium pump 100 pushes the Avastin outthrough the injector spines 108 at its most extreme extension point.

When the cranium pump 100 is expanding or is in its intake stroke, theinner membrane 107 collapses back to its original shape and thusretracts the injector spines 108 to their original position just outsideof the outer membrane 106. When the injector spines 108 are retracted,the pressure differential of the cranium pump 100 will necessarily drawin a small amount of surrounding cerebral fluid into a sampling cavity111. This is deemed beneficial however since the cerebral fluid will beeventually mixed with the Avastin and thus increasing the diffusion rateof the Avastin when it is pushed out of the injector spines 108 in anyof the subsequent supply strokes. This process of extending andretracting the injector spines 108 is repeated for as long as thecranium pump 100 is activated.

Returning to FIG. 13 c, the outer membrane 106 further comprises aplurality of micro pores 112 distributed throughout its entire surface.When the pump 100 is in the intake stroke, cerebral fluid is drawn intothe pump 100 through the micro pores 112 due to the pressuredifferential that exists between the inside of pump 100 and thesurrounding area outside of the pump 100. The amount of cerebral fluidthat is drawn through the micro pores 112 is kept separated from themedication reservoir 129 by the inner membrane 107 and the lowerportions of the injection spines 108. The volume of cerebral fluid thatis then contained between the inner membrane 107 and outer membrane 106then forms a sampling cavity 111. The components of cranium pump 100 ispreferably composed of silicone, as this is the material currently usedfor ventriculoperitoneal shunts. However additional materials such asbiodegradable material or other composites may be used without departingfrom the original spirit and scope of the invention.

The detailed parts of the pump head 103 and pump solenoid 104 assembliesare shown in FIGS. 15 a-16 b. In FIG. 15 a, the assembly is comprised ofa coil 119 which can generate magnetic fields either reinforcing oropposing the magnetic field of a permanent magnet 118. The permanentmagnet 118 is made of NbFe35 ceramic material however other materialsmay be used without departing from the original scope and spirit of theinvention. The coil 119 may then be pulled or pushed away from thepermanent magnet 118 depending on the current polarity of the coil 119.The coil 119 is coupled to a bobbin 120 and is constructed from aplurality of small (40 AWG) windings. The bobbin 120 is composed ofseveral layers of bobbin washers 121. Because bobbin 120 is attached tothe flexile skin-like material of the inner membrane 107, the coil 119movement translates into an increase or decrease of pressure on themedication reservoir 129.

Controlling the amount of electrical current that passes through thecoil 119 produces variable and regulated medication pressure which inturn adjusts the amount of Avastin passing through a plurality ofinjector spines 108 described above. Conversely, the controlled movementof the coil 119 acts as a pumping function serving to provide suction tothe outer membrane 106 of the pump and thus draw in surrounding cerebralfluid from the patient.

The apparatus uses a method similar to respiration to not only pumpdrugs into the brain, but also to sample the immediate area by creatinga negative pressure in the sampling cavity 111. As can be seen in FIG.12, the pump solenoid 104 and pump head 103 use a magnet 118 and coil119 as a solenoid to create attraction or repulsion between the pumphead 103 and the bobbin 120. This motion is then translated to thecranium pump 100. The outer membrane 106 is made of a more ridged durrasilicon rubber than the inner membrane 107. When the pressure isreversed by the pump solenoid 104, because the inner membrane 107 issofter than the outer membrane 106, the gap between the membranesincreases and the negative pressure sucks in the cerebral fluids throughthe aspirator micro-pores 112 around the spines 108 on the outermembrane 106. Turning back to FIGS. 15 a and 15 b, this sample fluidthen gets removed between a sampling washer 115 through samplingcollection ducts 128 in a delivery/sampling head 114 and out through aconnector plate 113.

The connector plate 113 has both a drug inlet 122 and a sampling tube123 connection. The connector plate 113 also comprises all theelectrical connections for the coil 119, the pressure sensor 131 (shownin FIG. 12) and the temperature sensors 132 (also shown in FIG. 12). Thetop of drug inlet 122 and the sampling tube 123 as well as varioussensor and coil connections can be seen in FIG. 11 b.

FIGS. 16 a and 16 b best show that the electrical connections aretransferred through a series of sensor and coil pins 126 through thedelivery/sampling head 114 to a plurality of sensor and coil connections125 in the inner medication reservoir 129. Connections to the coil 119are made with insulated flexible wire 130 (shown in FIG. 12).

Turning back to FIGS. 16 a and 16 b, the inner and outer membranes 107,106 are attached and compressed by washers 121 to the bobbin 120. Thebobbin 120 freely travels over the permanent NdFeB magnet 118. Themagnet 118 is permanently coupled to the delivery/sampling head 114. Theinner and outer membranes 107, 106 are also coupled directly to thedelivery/sampling head 114. The sampling washer 115 and the bobbin 120also provide the necessary gap of 0.020 inch for the medicationreservoir 129. A compression nut 117 compresses an inner membrane washer116 to clamp the inner membrane 107 against the delivery/sampling head114. As seen in FIG. 15 b, the delivery/sampling head 114 also comprisesa drug dispersion tube 124 which releases the Avastin or mixture ofmedicating agents and Avastin to be administered to the patient into themedication reservoir 129.

Turning back to FIG. 10 a, at the head of the cranium pump 100, the pumphead assembly 103 located there is coupled to a seal connector 102 via aseries of fluid lines and electronic connections enclosed in apump-to-seal interconnect 101. The seal connector 102 is essentially avalve that controls the amount of fluid that is permitted to enter orleave the pump 100. When more Avastin is needed, the seal connector 102opens and allows the Avastin to travel through the pump-to-sealinterconnect 101 and enter the medication reservoir 129 below. When thecorrect amount of Avastin has been applied, the seal connector 102closes and all incoming fluid flow stops. Additionally, the sealconnector 102 houses a suction nozzle (not shown) that applies suctionto the sampling cavity 111 and draws up recently acquired cerebral fluidup and out of the pump 100 and through the seal connector 102.

FIGS. 10 b and 10 c further depict the pump mode 145 and supply mode 144as it is employed by the cranium pump 100. FIGS. 10 b and 10 c depictthe electrostatic muscle 64 in its closed state 134 which is also thesupply mode 144, where the Avastin or BRM are pumped out and transportedfrom the cranium pump 100 to the desired tumor site or biological tissueof interest.

In FIG. 10 b, the inlet nozzle is shown as 136, while an increasingchamber volume 141 is taking place. The increase in chamber volumecauses flow 138 from the inlet 136 to enter the chamber 142 and at thesame time, there is a small amount of fluid which flows from the outlet137 into the chamber 142 as well. However, because of the venturi actionof the inlet 136 and the outlet 137, the total net flow is from thecranium pump 100 into the chamber 142. In this case, the inlet 136exhibits a diffuser action 143 and the outlet 137 exhibits a nozzleaction 140.

FIG. 10 c exhibits the electrostatic muscle 64 in its open state 135,which is also the pump mode 145. In this case there is a decrease inchamber volume 151, which causes a net flow to take place from thechamber 150 to the tumor site 41 through the outlet 148. Although thereis a small amount of flow 147, from the chamber 150 to the inlet, thenet flow is substantial and is from the chamber 150 to the tumor site41. In this mode, the inlet 147 exhibits a nozzle action, 152 and theoutlet exhibits a diffuser action 149.

Turning to FIG. 1 a, a delivery hose 200 is coupled to the sealconnector 102 and a CPD 1 portion of the apparatus. The delivery hose200 thus serves as a conduit between the pumping and analyzing portionsof the current invention and houses a refill line, a return sample fluidline, and several electronics connections for various sensors and thecoil 119.

After the cranium of the patient has been opened and the skull and durahave been successfully breeched, the tumor, or as much of the tumor aspossible, is removed. The soft cranium pump 100 is then placed in theresulting cavity, and the skull cap is reattached. As can be clearlyseen, the pump 100 is positioned on the patient's brain beneath both thedura and skull of the patient. The seal connector 102 is coupled to pump100 and is firmly embedded within the dura of the patient with the topportion of the shunt protruding from the skull. The delivery hose 200 iscoupled to the seal connector 102 and leads away from the pump 100 anddown the back of the neck of the patient underneath the skin. Thedelivery hose 200 lies beneath the scalp of the patient for the entiredistance between the seal connector 102 and the point where the catheteris connected to the analyzer 1 at the clavicular head. The purpose formaintaining the catheter 200 beneath the scalp is to give the patient asense of normalcy and confidence while they are undergoing treatment.

FIG. 1 b shows an external controller 300 which communicates with thechemotherapy pump device (CPD) 1. The CPD 1 communicates with theexternal controller 300 by the use of RF transmitter 304 and itsassociated antenna 302 and RF receiver 303 with its associated antenna301. After implantation of the CPD 1 subcutaneously inside the patient39, the system allows for programmability of the device in order todispense the Avastin in proper intervals over time and in the prescribeddoses. Once the CPD 1 and cranium pump 100 is implanted and is inoperation, the clinician may decide to change the parameters of theoperation such as the amount of medication dispensed onto the tumor siteor the time intervals associated with the dispense process. Theclinician communicates with the internal electronics of CPD 1 using anexternal controller 300 shown in FIG. 1 b, which may be in the form of adesktop computer or any other similar appropriate device. The externalcontroller 300 is able to communicate with the microcontroller in CPD 1through its own microcontroller 305 via RF transmitter 304, its antenna302, and the RF receiver 303 and its antenna 301, or via the serialcommunication port 307, located in the external controller 300. The newsets of commands are then transferred to the cranium pump 100. These newcommand data are then stored in the memory of the microcontroller of CPD1, which is now programmed anew to perform the procedure as coded in thenew instruction set.

In one embodiment, the external controller 300 is used to implementcomputer software that provides preoperative simulation of the infusionof Avastin and other intratumoral infusates to maximize infusionefficiency and minimize local toxicity to the adjacent brain fromleakage of the infusate into the normal tissue by means of a diffusionmodel. The diffusion model is used to describe the drug dispersion withthe brain's extracellular space due to both diffusion and convection.Specifically, brain geometry, drug properties, catheter dimensions andplacement, and injection method are considered in this model. Otherterms such as drug decomposition, chemical kinetic reaction, andbio-elimination can be incorporated to improve the accuracy of theprediction model.

In the first step, the patient-specific diffusion tensor imaging (amethod of MRI) is used to construct a brain tumor model with accurategeometry (sharp boundaries and surfaces of the substructures). In thesecond step, the brain region is partitioned into small discrete volumegrids. In the third step, a set of equations and boundary conditionsdescribe flow physics and mass transfer between the finite volumes inthe brain region. In the final step, the equations are solvednumerically over the finite volume and the boundaries between theadjacent volumes.

The patient specific brain imaging data not only provides accurate sizeand shape of the tumor region but also permit reconstruction ofphysiologically consistent substructures and boundaries between regionsin the brain. Brain and tumor tissue properties such as porosity,tortuosity, diffusivity, permeability, and hydraulic conductivityparameter's can be estimated from the brain location and referenceliterature. These parameters combined with the catheter placement andorientation respect to the tumor region allow estimation of locationspecific parameters such as diffusivity tensor, permeability tensor, andhydraulic conductivity tensor values required in the flow and masstransfer equations.

The brain including tumor region is partitioned into small triangularand quadrilateral elements using Delaunay triangulation. Each smallfinite volume is linked to its neighbors so as to form a logicallyconnected computational mesh, which can be generated by grid generationsoftware such as Fluent 2007. The grid sizes need to be large enough tominimize the number of volume elements for calculations yet small enoughto be able to spatially resolve the anatomical properties of the tumorarea. A typical simulation consists of approximately 20,000 to 30,000volume elements distributed in the region covering about one quarter ofthe brain (300 cc). The flow and mass transfer equations are enforcedover the computational domain consisting of these meshes.

The drug delivery to the brain is simply modeled as inserting aqueoussolution consisting of drug solutes into porous brain tissues via aninfusion catheter. The aqueous solution is assumed to be anincompressible Newtonian fluid whose motion can be described by the massand momentum conservation equation. Additionally, the drug distributionis described by the species transport and chemical kinetics equations.The diffusion model consists of two parts: the flow inside the catheterand the flow in porous brain tissues.

For the flow inside the catheter, the model divides the space inside thelumen of the catheter into small finite elements. The fluid flow betweenthe finite elements is modeled with the continuity and Navier-Stokesequations as shown in Equations 1 and 2, respectively. The continuityequation (Eq 1) describes that the fluid is incompressible.

{right arrow over (∇)}·(ρ {right arrow over (ν)}_(f))=0   (1)

The Navier-Stokes equation (Eq 2) describes that the momentum of thefluid flow is conserved. It states that any change in fluid velocity inthe catheter (the left-hand side of the equation) is due to the pressuregradient (caused by the pumps) and resistance of the flow due to fluidviscosity.

$\begin{matrix}{{\rho \left( {\frac{\partial{\overset{\rightarrow}{v}}_{f}}{\partial t} + {{\overset{\rightarrow}{v}}_{f} \cdot {\overset{\rightarrow}{\nabla}{\overset{\rightarrow}{v}}_{f}}}} \right)} = {{- {\overset{\rightarrow}{\nabla}p}} + {\mu {{\overset{\rightarrow}{\nabla}}^{2}{\overset{\rightarrow}{v}}_{f}}}}} & (2)\end{matrix}$

The movement of the drug molecules inside the catheter due to the flowcan be modeled with the species transport equation as shown in Equation3. It states that the change in concentration of the molecules due todiffusion and convection (the left-hand side of the equation) depends onthe divergent of the product of the diffusivity and concentrationgradient of the molecules in the fluid.

$\begin{matrix}{{\frac{\partial C_{f}}{\partial t} + {{\overset{\rightarrow}{v}}_{f} \cdot {\overset{\rightarrow}{\nabla}C_{f}}}} = {\overset{\rightarrow}{\nabla}{\cdot \left( {D_{b}{\overset{\rightarrow}{\nabla}C_{f}}} \right)}}} & (3)\end{matrix}$

The flow inside the brain is modeled as the fluid flow in a porousmedium. The brain is partitioned into small finite elements and the flowbetween these elements is modeled with the continuity equation andDarcy's Law as shown in Equations 4 and 5, respectively. The continuityequation (Eq 4) describes that the loss of fluid in the flow is due tothe absorption into the porous medium. The fluid velocity in tissue isrelated to average fluid velocity through porous tissue, {right arrowover (ν)}_(t)=ε {right arrow over (ν)}_(p), through the porosity. At thetip of the catheter, the average fluid velocity is the same as the fluidvelocity coming out of the catheter: {right arrow over (ν)}_(p)={rightarrow over (ν)}_(f). The amount of fluid loss captured in the sink termis a function of the difference between the interstitial fluid pressureand the venous pressure: S_(B)=f(p−p_(ν)).

{right arrow over (∇)}·(ρ {right arrow over (ν)}_(t))=S_(B)   (4)

The fluid dynamics in the porous brain is embodied in the Darcy's Law(Eq 5), which states that the momentum of the fluid flow is conserved.It states that any change in fluid velocity in the brain (the left-handside of the equation) is due to the pressure gradient (caused by theflow out of the catheter) and resistance of the medium to the flow.

$\begin{matrix}{{\frac{\rho}{ɛ}\left( {\frac{\partial{\overset{\rightarrow}{v}}_{t}}{\partial t} + {{ɛ^{- 1}\left( {{\overset{\rightarrow}{v}}_{t} \cdot \overset{\rightarrow}{\nabla}} \right)}{\overset{\rightarrow}{v}}_{t}}} \right)} = {{- {\overset{\rightarrow}{\nabla}p}} - {{\overset{\rightarrow}{v}}_{t}}}} & (5)\end{matrix}$

The movement of the drug molecules inside the brain due to the flowdescribed in Eq 5 can be modeled with the species transport equation asshown in Equation 6. It states that the change in concentration of themolecules due to diffusion and convection (the left-hand side of theequation) depends on the divergent of the product of the diffusivitytensor of the brain medium and concentration gradient of the moleculesin the fluid. The accuracy of the model can be improved by incorporatingthe loss of drug molecules due to decomposition and bio-elimination.

$\begin{matrix}{{{ɛ\frac{\partial C_{t}}{\partial t}} + {{\overset{\rightarrow}{v}}_{t} \cdot {\overset{\rightarrow}{\nabla}C_{t}}}} = {{\overset{\rightarrow}{\nabla}{\cdot \left( {_{e}{\overset{\rightarrow}{\nabla}C_{t}}} \right)}} + {R\left( {C_{t},\overset{\rightarrow}{x}} \right)} + {S\left( {C_{t},\overset{\rightarrow}{x}} \right)}}} & (6)\end{matrix}$

The completeness of the diffusion model is captured in the boundarycondition assumptions listed below. At the catheter inlet, the infusionflow rate or pressure and concentration of drug are assumed to beconstant. At the interior wall inside the lumen of the catheter, theflow is assumed no slip,

${\frac{\partial p}{\partial n} = 0},$

and the drug doesn't penetrate (zero flux) into the catheter wall,{right arrow over (n)}·{right arrow over (∇)}C_(f)=0 and {right arrowover (ν)}_(f)=0. At the outer surface of the catheter, the same boundaryconditions are assumed as in the inside. At the catheter tip, thecontinuity of flow is assumed: {right arrow over(ν)}_(f)|_(lumen)={right arrow over (ν)}_(Cout)={right arrow over(ν)}_(t), and, p_(lumen)=p_(Cout), and C_(f)|_(lumen)=C_(f). At thelateral ventricles or capillary surfaces, the fluid pressure is the sameas the pressure of the Cerebrospinal fluid

(CSF). No fluid flow through the ventricle and capillary walls, {rightarrow over (n)}·{right arrow over (∇)}ν_(x)=0, {right arrow over(n)}·{right arrow over (∇)}ν_(y)=0. Only the mass transfer through thepermeable ventricle and capillary walls is assumed: −D_(e)({right arrowover (n)}·{right arrow over (∇)}C_(t))=k(C_(t)−C_(∞)). Molecule transferthrough permeable boundary is only one way; drug molecules can leave butcannot return. Bio-elimination “sink term” is assumed as a function ofthe difference between interstitial pressure and venous pressure:S_(B)=f(p−p_(ν))

The six partial differential equations (Eq 1-6) are applied to thediscrete volumes in the model to produce a set of non-linear algebraicequations for the entire brain model. These equations are solved withproper boundary condition using the iterative Newton-Krylov method andsimulated using commercial fluid dynamics software such as Fluent.

The microcontroller located in CPD 1 and implanted inside the patient'sbody 39 communicates with the external controller 300 via RF transmitter304 and RF receiver 303 thereby sending its collected data to theexternal controller 300. This feature enables the clinician to collectdata and to determine the state of the patient throughout the period oftreatment. These data are stored inside the external controller 300providing chart history of the treatment status of the parametersassociated with the tumor site. The CPD 1 transmits data for collectionand storage. The external controller 300 is controlled by the user viathe settings in control 308 and it also displays the amount of Avastindispensed over time by the cranium pump 100 on its display 309. Datacollected in this manner can be used to correlate behavior pattern of aparticular patient and his or her chart history. One can write a datacollection and analysis program which can be displayed by the externalcontroller 300. Once the data are collected from the CPD 1, the externalcontroller 300 or the host PC can then plot the data on a time scale andanalyze the data further. It is significantly better to correlatebetween the input and the output or between cause and effect to mirrorthe action of the cranium pump 100 and its host tumor site. Such data inthe form of historical plot of cause and effect benefit the patient 39and aide in future research. The entire unit as shown in the figure isrun by power obtained from its power source 306.

FIG. 1 c is an illustration of a patient 39 with tumor of the formglioma with the implanted pump 100. The external controller 300 with itsassociated serial port 307 and receiver and transmitter antennae 303 and304 respectively is shown in its bidirectional communication model withthe implanted CPD 1 via the RF path 310.

Turning to FIG. 4 a, the CPD 1 comprises a delivery connector 7 wherethe delivery hose 200 couples with the CPD 1. The delivery connector 7contains a drug outlet 4, a sample return 5, and a plurality of sensorconnections 6 for controlling the pump unit 100 and for analyzing thesample fluid that is obtained from the cranium of the patient. The drugoutlet 4 is the aperture in which Avastin or mixtures of medicatingagents with Avastin are sent from the CPD 1 through the delivery hose200. Similarly, the sample return 5 is the aperture where cerebral fluidthat has been collected by pump 100 is returned by the delivery hose 200and enters the CPD 1 for analysis. The process by which the external CPD1 sends Avastin or medicating agents mixed with Avastin and receivessample fluid obtained from the patient through the delivery hose 200 isexplained in further detail below.

Up to four drug ampoules 2 (FIG. 2) can be deposed on the bottom portion10 of the external CPD 1 in four separate ampoule bays 8 as depicted inFIG. 3 d. It is to be expressly understood that fewer or additionalampoule bays may be present without departing from the original spiritand scope of the invention. To introduce Avastin into the CPD 1, a drugampoule 2 is inserted into the ampoule bay 8. Drug needles 18 extendingfrom the interior of the CPD 1 shown in FIG. 7 a penetrate the ampoules2 and carry the Avastin. The CPD 1 then draws in the Avastin in a seriesof steps that are described below.

Turning to FIG. 6, the interior of the CPD 1 is comprised of twoassemblies; a pump electronics assembly 12 and an induction chargerassembly 11. The pump electronics assembly 12 and the induction chargerassembly 11 are both housed within the external CPD 1 and are joined byan electronics interconnect cable 13 as best seen in FIGS. 7 a and 7 b.

The pump electronics assembly 12 is shown in greater detail in FIGS. 8 aand 8 b. As seen in FIG. 8 b, the pump electronics assembly 12 containsa drug delivery CPU 27 that stores its program and data into two FLASHmemories 28. Pre-stored information such as look-up tables and the likeare stored on the FLASH memories 28. The drug delivery CPU 27 runs apre-installed intelligent chemo delivery software program and controlsan ampoule pump integrated circuit 20, a return pump integrated circuit19, and a delivery valve drift integrated circuit 22 as seen in FIG. 8a. The drug delivery CPU 27 also communicates with a lab-on-a-chip 21and receives important treatment data such as sample temperature datathrough the sensor inputs 6 in the delivery connector 7 seen best inFIG. 6.

The drug delivery CPU 27 is pre-programmed and is capable oftransmitting data through a Bluetooth® transceiver 29. The Bluetoothtransceiver 29 is connected to a Bluetooth® antenna 30. A user orqualified physician who wishes to change the patient's drug regimen froma remote location first sends the data to the patient. The sentinformation is then picked up by the Bluetooth® transceiver 29 andantenna 30 and is then stored on the FLASH memory chips 28. When thedrug delivery CPU 27 retrieves information from the FLASH memory chips28 it adjusts the drug regimen (dose, scheduling, etc.) according to theuser's data instructions.

The external CPD 1 is capable of delivering up to four different drugssimultaneously with high accuracy in the following manner: The pumpelectronics assembly 12 of FIG. 8 a comprises up to four piezoelectricpumps 17 driven by a corresponding ampoule pump integrated circuit 20that together pump the Avastin out of the ampoule 2. The use andmanufacture of piezo pumps are well known to those in the art. Fewer oradditional piezo pumps 17 than what is depicted in FIG. 8 a may be usedwithout departing from the original spirit and scope of the invention.The pump needles 18 are sufficiently long enough so that when a drugampoule 2 is attached to the piezo pump 17 as depicted in FIG. 2, theAvastin at the bottom of the ampoule may be accessed. Pump needles 18coupled to the piezoelectric pumps 17 penetrate the ampoules 2 and thepiezoelectric pump 17 pumps the Avastin through a drug manifold tube 24and into a delivery valve 15 and out through the drug delivery connector7. The delivery valve 15 is regulated by a delivery valve driverintegrated circuit 22 which is controlled by the drug delivery CPU 27.The Avastin, after being pumped through the delivery connector 7, thenenters into the delivery hose connector 37 (FIG. 5) via the drug output4 on the delivery connector 7 depicted in FIG. 4 b. The Avastin is thenpumped through the delivery hose 200 and into the cranial pump unit 100via the seal connector 102. In FIG. 5, the delivery hose 200 couples tothe CPD 1 via a delivery hose connector 37.

The external CPD 1 is fully programmable and runs intelligent softwareto determine what and how much drug is required. The regulation loop ofthe intelligent drug delivery system uses a return sample of fluids fromthe “delivery area” to determine the necessary response. In FIG. 5, thereturn sample fluid obtained from the patient travels through thedelivery hose 200, through the delivery hose connector 37, and thenenters delivery connector 7 through the sample return 5 as shown in FIG.4 b. Turning to FIG. 8 a, after the sample fluid passes from thedelivery connector 7, the sample fluid enters the delivery valve 15. Thenegative pressure necessary to pump the sample is created by the returnpiezoelectric pump 16 that is powered by a return pump driver integratedcircuit 19. The fluid sample then travels from the delivery valve 15into a return pump input tube 25 and into a lab-on-a-chip 21 that sensesthe chemical composition of the sample. The return piezoelectric pump 16continues pumping the sample fluid through itself and back out into areturn output pump tube 23. The sample fluid is then mixed together withthe delivery drug in the delivery valve 15, to continue a closed loopcycle to be returned to the collection site.

The second main assembly, the induction charger assembly 11, is depictedin greater detail in FIGS. 9 a and 9 b. The induction charger assembly11 provides with a means for charging a lithium ion battery 14 (shown inFIG. 5). An induction coil 38 coupled to the induction chargerelectronics assembly 11 receives a high frequency (50 Khz) inducedmagnetic field from a similar charging coil from an external batterycharger device (not shown). The induction coil 38 is coupled to arectifier 35 shown in FIG. 9 b. The rectifier 35 converts the highfrequency voltage to a DC voltage that is filtered by an inductor 34 andcapacitors 33. A battery charger controller 32 regulates the charging ofthe battery 14. The charger connector 36 is both for powering theelectronics as well as charging the lithium ion battery 14. The battery14 is appropriately sized to provide sufficient power for days ofservice without the need of charging.

The lithium ion battery 14 preferably has an “L” shape as shown in FIG.6 so as to leave sufficient space available for the pump needles 18 anddrug ampoules 2 within the housing of the CPD 1 and is sized to providesufficient power for days of service without the need of re-charging.However it is to be expressly understood that other varieties ofbatteries with various life spans and shapes may also be used withoutdeparting from the original scope and spirit of the invention. Thelithium ion battery 14 is coupled directly to the housing of the CPD 1and is removable so that when the stored energy has been depleted fromthe battery 14, it may be easily replaced.

Filling the ampoules 2 with Avastin and having the Avastin thendelivered intratumor by the pump 100 and its injector spines 108,eliminates the blood brain barrier as a potential obstacle. As discussedabove Avastin is an antibody and thus would normally have a difficulttime getting to the glioma cells directly without the pump 100penetrating the brain blood barrier. Delivering the Avastin directlyinto the tumor also allows for more concentrated doses which eliminatesthe side effects associated with the systemic intravenous delivery ofAvastin listed above, including intracerebral hemorrhages which can becatastrophic to the patient. Finally, the lab-on-a-chip 21 comprisesmeans for directly monitoring the VEGF levels in the tumor. Avastin, asdisclosed above, lowers the levels of VEGF in the tumor. Thus when thelab-on-a-chip 21 gives a current VEGF level, it is also thereforesimultaneously giving a direct measurement and assessment of theeffectiveness of the intratumor administration of the Avastin.

In patients in whom a resection cannot be performed, an alternativeembodiment of the current invention involving a multidelivery catheter200 is employed. A method for delivering intratumoral Avastin into thetumor in a patient comprises surgically implanting a multideliverycatheter 200 beneath the skull and dura of the patient into a treatmentsite. The multidelivery catheter 200 is then coupled to an externalanalyzer unit 300. The external analyzer unit 300 is the same externalanalyzer unit 300 described above with regard to the previousembodiment. The multidelivery catheter 200 is then operated within thetreatment site of the patient in order to infuse the intratumoralAvastin to the treatment site. The multidelivery catheter 200 is thenused to suction in a sample of cerebral fluid from the treatment siteand transfer it to the external analyzer unit 300. In the same manner asdescribed above with regard to the previous embodiment, the externalanalyzer unit 300 is then used to track and monitor the progress of thepatient's treatment via the external analyzer unit 300. Additionally inthe same manner as described above with the previous embodiment, theexternal analyzer unit 300 comprises the means for altering and changingthe patient's treatment. Finally, a reservoir of intratumoral Avastinthat is located within the external analyzer unit 300 may be refilledand replenished as needed.

Also as similarly described above, the external analyzer unit 300comprises means for displaying the amount of intratumoral Avastindispensed over time by the multidelivery catheter 200 within thetreatment site.

In one particular embodiment, the suctioning in of the sample cerebralfluid from the treatment site comprises suctioning in the samplecerebral fluid in at least two proximal ports (not shown) defined in theproximal end of the multidelivery catheter 200. The means for trackingand monitoring the progress of the patient's treatment by the externalanalyzer unit 300 further comprises passing the sample cerebral fluidthrough a means for spinal fluid analysis in the external analyzer unit300. The sample of cerebral fluid passes through a means of analysis onthe external analyzer unit 300 that comprises means for measuring theeffectiveness of the administration of the intratumoral Avastin.

In another embodiment, the method step of measuring the effectiveness ofthe intrtumoral Avastin administration further comprises displaying theresults obtained from the means of the analyzer unit on a display.

In an alternative embodiment, the external analyzer unit 300 furthercomprises means for providing a preoperative simulation of the infusionof the intratumoral Avastin and other intratumoral infusates to maximizeefficiency and minimize toxicity by means of a diffusion model.

The external analyzer unit 300 further comprises entering commandfunctions and data into the external analyzer unit 300 from a remotekeypad (not shown) and displaying the commands on a display 309. Theentering of command functions may comprise sending command functions anddata to the external analyzer unit 300 by means of a Bluetooth®transceiver and antenna.

The refilling and replacing of the reservoir of intratumoral Avastinlocated in the analyzer unit also comprises refilling and replacing atleast four drug ampoules coupled to the analyzer unit, wherein at leastone of the four drug ampoules is for Avastin.

FIG. 17 is a functional circuit diagram further illustrating therelationship between the elements of CPD 1 described above.

Many alterations and modifications may be made by those having ordinaryskill in the art without departing from the spirit and scope of theinvention. Therefore, it must be understood that the illustratedembodiment has been set forth only for the purposes of example and thatit should not be taken as limiting the invention as defined by thefollowing invention and its various embodiments.

For example, one skilled in the art may produce a device with fewer oradditional drug ampoule bays or piezoelectric pumps without departingfrom the original scope and spirit of the invention.

Therefore, it must be understood that the illustrated embodiment hasbeen set forth only for the purposes of example and that it should notbe taken as limiting the invention as defined by the following claims.For example, notwithstanding the fact that the elements of a claim areset forth below in a certain combination, it must be expresslyunderstood that the invention includes other combinations of fewer, moreor different elements, which are disclosed in above even when notinitially claimed in such combinations. A teaching that two elements arecombined in a claimed combination is further to be understood as alsoallowing for a claimed combination in which the two elements are notcombined with each other, but may be used alone or combined in othercombinations. The excision of any disclosed element of the invention isexplicitly contemplated as within the scope of the invention.

The words used in this specification to describe the invention and itsvarious embodiments are to be understood not only in the sense of theircommonly defined meanings, but to include by special definition in thisspecification structure, material or acts beyond the scope of thecommonly defined meanings. Thus if an element can be understood in thecontext of this specification as including more than one meaning, thenits use in a claim must be understood as being generic to all possiblemeanings supported by the specification and by the word itself.

The definitions of the words or elements of the following claims are,therefore, defined in this specification to include not only thecombination of elements which are literally set forth, but allequivalent structure, material or acts for performing substantially thesame function in substantially the same way to obtain substantially thesame result. In this sense it is therefore contemplated that anequivalent substitution of two or more elements may be made for any oneof the elements in the claims below or that a single element may besubstituted for two or more elements in a claim. Although elements maybe described above as acting in certain combinations and even initiallyclaimed as such, it is to be expressly understood that one or moreelements from a claimed combination can in some cases be excised fromthe combination and that the claimed combination may be directed to asubcombination or variation of a subcombination.

Insubstantial changes from the claimed subject matter as viewed by aperson with ordinary skill in the art, now known or later devised, areexpressly contemplated as being equivalently within the scope of theclaims. Therefore, obvious substitutions now or later known to one withordinary skill in the art are defined to be within the scope of thedefined elements.

The claims are thus to be understood to include what is specificallyillustrated and described above, what is conceptionally equivalent, whatcan be obviously substituted and also what essentially incorporates theessential idea of the invention.

1. A method for delivering Avastin into a brain tumor in a patientcomprising: surgically implanting a cranium pump beneath the skull anddura of the patient's brain into a treatment site; coupling the craniumpump to an analyzer unit via a fluid exchange catheter; operating thecranium pump within the brain of the patient in order to infuse Avastinto the treatment site; suctioning in a sample of cerebral fluid from thetreatment site and transferring it to the analyzer unit; tracking andmonitoring the progress of the patient's treatment via the analyzerunit; altering and changing the patient's treatment by controlling theanalyzer unit; and refilling and replacing a reservoir of Avastinlocated in the analyzer unit.
 2. The method of claim 1 where operatingthe cranium pump comprises contracting and expanding an inner membranereservoir in the cranium pump by oscillation of a magnetic solenoid. 3.The method of claim 1 where suctioning the sample of the patient'scerebral fluid further comprises suctioning the sample cerebral fluidinto an intra-membrane reservoir defined between an outer and innermembrane in the cranium pump by the oscillation of a magnetic solenoid.4. The method of claim 1 where tracking and monitoring the progress ofthe patient's treatment further comprises passing the sample of cerebralfluid through a means for cerebral fluid analysis in the analyzer unit.5. The method of claim 4 where passing the sample of cerebral fluidthrough a means of analysis further comprises measuring theeffectiveness of intratumoral Avastin administration by means of theanalyzer unit.
 6. The method of claim 5 where measuring theeffectiveness of intratumoral Avastin administration further comprisesdisplaying the results obtained from the means of the analyzer unit on adisplay.
 7. The method of claim 1 further comprising providing apreoperative simulation of the infusion of Avastin and otherintratumoral infusates to maximize efficiency and minimize toxicity bymeans of a diffusion model.
 8. The method of claim 1 where altering andchanging the patient's treatment by controlling the analyzer unitfurther comprises entering command functions and data into the analyzerunit from a remote keypad and displaying the commands on a display. 9.The method of claim 8 where altering and changing the patient'streatment by controlling the analyzer unit further comprises sendingcommand functions and data to the analyzer unit by means of a Bluetooth®transceiver and antenna.
 10. The method of claim 1 where refilling andreplacing the reservoir of Avastin located in the analyzer unit furthercomprises refilling and replacing at least four drug ampoules coupled tothe analyzer unit, wherein at least one of the four drug ampoules is forAvastin only.
 11. A method for delivering Avastin into a brain tumor ina patient comprising: surgically implanting a multidelivery catheterbeneath the skull and dura of the patient's brain into a treatment site;coupling the multidelivery catheter to an analyzer unit; operating themultidelivery catheter within the brain of the patient in order toinfuse Avastin to the treatment site; suctioning in a sample of cerebralfluid from the treatment site and transferring it to the analyzer unit;tracking and monitoring the progress of the patient's treatment via theanalyzer unit; altering and changing the patient's treatment bycontrolling the analyzer unit; and refilling and replacing a reservoirof Avastin located in the analyzer unit.
 12. The method of claim 11where tracking and monitoring the progress of the patient's treatmentvia the analyzer unit further comprises displaying the amount of Avastindispensed over time by the multidelivery catheter within the treatmentsite.
 13. The method of claim 11 where suctioning the sample of thepatient's cerebral fluid further comprises suctioning the samplecerebral fluid into an intra-membrane reservoir defined between an outerand inner membrane in the inflatable balloon by the inflation andcontraction of the inflatable balloon.
 14. The method of claim 11 wheretracking and monitoring the progress of the patient's treatment furthercomprises passing the sample of cerebral fluid through a means forcerebral fluid analysis in the analyzer unit.
 15. The method of claim 14where passing the sample of cerebral fluid through a means of analysisfurther comprises measuring the effectiveness of intratumoral Avastinadministration by means of the analyzer unit.
 16. The method of claim 15where measuring the effectiveness of intratumoral Avastin administrationfurther comprises displaying the results obtained from the means of theanalyzer unit on a display.
 17. The method of claim 11 furthercomprising providing a preoperative simulation of the infusion ofAvastin and other intratumoral infusates to maximize efficiency andminimize toxicity by means of a diffusion model.
 18. The method of claim11 where altering and changing the patient's treatment by controllingthe analyzer unit further comprises entering command functions and datainto the analyzer unit from a remote keypad and displaying the commandson a display.
 19. The method of claim 18 where altering and changing thepatient's treatment by controlling the analyzer unit further comprisessending command functions and data to the analyzer unit by means of aBluetooth® transceiver and antenna.
 20. The method of claim 11 whererefilling and replacing the reservoir of Avastin located in the analyzerunit further comprises refilling and replacing at least four drugampoules coupled to the analyzer unit, wherein at least one of the fourdrug ampoules is for Avastin only.